Therapeutic utilization of 17alpha-methyl-delta2-5alpha-androstene-11beta, 17beta-diol



United States Patent 3,287,221 THERAPEUTIC UTILIZATION OF 17a-METHYL-A 5a-ANDROSTENE-11p,17B-DIOL Georges Muller, N ogent-sur-Marne, and Andr Poittevin,

Les Lilas, France, assignors to Roussel-Uclaf, Paris, 5 France, a corporation of France No Drawing. Filed July 30, 1964, Ser. No. 386,432 Claims priority, application France, Aug. 5, 1963, 3 7

9 Claims. (c1. 16774) The present invention relates to a novel 17a-methyl steroid, the 17a-methyl-A -5a-androstene-115,17B-diol of the formula:

CH3 OH The invention also relates to the process of producing the on, OH

rro-

0H, CH

Another object of the invention is the development of a process for the production of a 17a-methyl steroid of the formula CH3 OH 3,287,221 Patented Nov. 22, 1966 which comprises the steps of reacting l7a-methyl-5u-androstane-3B,l15,17B-triol with an organic hydrocarbon sulfonic acid chloride of the formula wherein R represents an organic hydrocarbon group having from 1 to 10 carbon atoms, in an organic solvent, subjecting the resulting compound of the formula wherein R has the above-assigned meaning, to the action of an alkaline agent in a solvent at elevated temperatures, and recovering said l7u-methyl steroid.

A further object of the invention is the production of intermediates, particularly a sulfonic acid ester of the formula wherein R represents an organic hydrocarbon group having from 1 to 10 carbon atoms.

- A yet further object of the invention is the production of a therapeutic composition consisting of a minor amount of a l7a-methy1 steroid of the formula CH; OH

on, on

and a major amount of an inert pharmaceutically-acceptable excipient.

A still further object of the invention is the development of a method for the treatment of anabolic deficiencies in warm-blooded animals which comprises administrating to the Warm-blooded animal a daily dose of from 7 'yI/kg. to 600 'y/kg. of a 17a-Inethyl steroid of the formu a CH 0H I CH These and other objects of the invention will become more apparent as the description thereof proceeds.

The process for the preparation of 17a-methyl-A -5a androstene-11B,17fi-diol, which is also a subject of the invention, is characterized essentially in that an organic hydrocarbon sulfonic acid chloride is reacted with 17ccmethyl-5a-androstane-3/3,11;3,17/8-triol. The 3B-sulfonate ester correspondingly formed is subjected to the action of an alkaline agent, and the desired 17a-methyl-A -5aandrostene-l 15,17f3-diol is isolated.

The reaction of the sulfonic acid chloride is conducted in an organic solvent, preferably in a solvent capable of neutralizing the hydrochloric acid produced, such as pyridine or other tertiary amines. The organic hydrocarbon sulfonic acid chloride is preferably of the formula wherein R represents an organic hydrocarbon group having from 1 to 10 carbon atoms, such as tosyl chloride (p-toluene sulfonic acid chloride) or mesyl chloride (methane sulfonic acid chloride). The reaction is conducted at temperatures from about 15 C. to about room temperature, preferably from about 5 C. to about +5 C. I

The alkaline agent, used for the introduction of the 2-3 double bond is preferably selected from the group consisting of alkali metal hydroxides and alkali metal carbonates. The reaction is conducted in a solvent at elevated temperatures, especially at reflux temperatures. An alkali metal hydroxide in an aqueous media can be utilized but preferably an alkali metal carbonate is used and more precisely lithium carbonate in dimethylformamide is preferred.

The following examples are illustrative of the invention. It is to be understood that other expedients known to those skilled in the art may be employed.

EXAMPLE I.PREPARATION OF 17LZ-METHYL- M-Sa-ANDROSTENE-l15,17fi-DIOL Step A: Preparation of 2,8-tosyloxy-17a-methyl-5a-androstane-I 1,6,1 7 3-diol.5 g. of 17u-methy1-5a-androstane- 3fl,11,8,17/3-triol (described in US. Patent No. 2,861,087), and 25 cc. of pyridine were introduced into a balloon flask under agitation and in a stream of nitrogen at room temperature. The mixture was cooled to -2 C., then 4.3 g. of tosyl chloride were added. The mixture was agitated for one hour at C. under a stream of nitrogen and thereafter allowed to stand overnight at 0 C. while continuously agitating. Then the mixture was poured over a mixture of ice and Water and allowed to stand at rest for a period of three hours. Next, the mixture was filtered. The precipitate was washed with water and dissolved in methylene chloride. The. organic phase was decanted, dried over magnesium sulfate and distilled to dryness under vacuum. The residue was recrystallized from methanol by heating and cooling. The crystalline precipitate was filtered, then washed with methanol and dried. 6.10 g. of 3B-tosyloxy-17a-methyl-5a-androstane- 115,17B-diol were thus obtained in the form of a product crystallized in needles. This product is very soluble in chloroform, soluble in acetone, slightly soluble in alcohol and insoluble in water, dilute aqueous acids and ether, has a melting point of 120 C. to 125 C. and a specific rotation [a] =+1 (c.=0.5% in chloroform).

This compound is not described in the literature.

Step B: Preparation of 17a-methyl-A -a-andr0stene- 11;.8,17B-diol.0.50 g. of lithium bromide were dissolved, in a balloon flask, in 2.5 cc. of dimethylformamide under agitation at room temperature. 0.50 g. of 3/3-tosyloxy- 17a-methyl-5a-androstane-11,3,17,8-diol were added, followed by 0.25 g. of lithium carbonate. The mixture was heated at reflux for a period of thirty minutes. Then the mixture was cooled to room temperature. 25 cc. of water and 2 cc. of acetic acid were added. The precipitate 4 formed was filtered, washed with water and dried at a temperature of C. 0.285 g. of 17a-methyl-A -5aandrostene-11fl,17fi-dio1 were thus obtained, having a melting point of 180 C. to 182 C. (being a yield of 89% The product was purified by recrystallization from petroleum ether. l7a-methyl-A -5m-androstene-l1 8,175- diol was thus obtained in the form of a product crystallized in colorless prisms. This product is very soluble in alcohol, acetone, benzene and chloroform, soluble in ether and insoluble in water, melts at 184 C. (Kofier block), and has a specific rotation [a] =+47 i1.5 (c.=0.9% in ethanol).

The IR. spectra shows:

Absence of carbonyl band Presence of a hydroxyl group A band towards 1,650 cm.- attributable to a-C=C double bond The NMR spectra conforms to the presence of a double bond in the 2-3 position.

Analysis.C H O molecular weight=304.46. Calculated: C, 78.89%; H, 10.59%. Found: C, 78.8%; H, 10.4.

This compound is not described in the literature,

As it has been indicated above, 17a-methyl-A -5a-androstene-11,8,17B-diol possesses interesting pharmacological properties. In particular, it possesses an important anabolic action while being practically devoid of an androgenic effect.

It may be used for the treatment in warm-blooded animals of protidic anabolism, asthenia, thinness and osteoporosis.

17a-methyl-A -5a-androstene-116,17/3-diol can be administered by oral, transcutaneous or rectal administration.

It can be prepared in the form of injectable solutions or suspensions, made up in ampoules or multiple dose phi-als; in form of tablets, coated tablets, drinkable solutes and suppositories.

The useful dosology is controlled between 707/ kg. and

EXAMPLE II.PHARMACOLOGICAL STUDY OF 17a-METHYL-A -5a-ANDROSTENE-1 15,17fl-DIOL Determination of the androgenic and anabolic activity These tests were conducted according to the Hershberger technique (Proc. Soc. Exp. Biol. Med. 1953, 83, slightly modified. This consisted in a daily administration of the compound under study to male rats, castrated at an age of 3 /2 weeks. The rats were treated, starting the day after the castration, for a period of ten days, and the animals were sacrificed on the eleventh day, 22 to 26 hours after the last administration. An autopsy was performed on the animals at the time of their death, and the organs of interest were dissected and weighed, particularly the levator muscle of the anus (levator ani) for the purpose of studying the anabolic action, and the ventral prostate gland and the seminal vesicles for the purpose of studying the simultaneous androgenic effect.

17a-methyl-A -5u-androstene-11,8,17 3-di0l, utilized in suspension in water containing carboxymethyl cellulose, was administered orally at doses of 0.214 mg., 1.070 mg. and 5 mg. per rat and per day. The results obtained were compiled in Table I hereafter. For purpose of comparison, the results obtained with 17a-methyl-testosterone, 17a-methyl-19-nor-testosterone and 17a-ethy1-19-nor-testosterone are also presented.

TABLE I Daily Seminal Ventral Fresh Treatment Dose vesicles, prostate, levator Li 1 mg. mg. anl, mg.

Control. 5. 3 ll. 6 18. 6 0. 219 {$2131 3:? it? 813 17a-methyl-19-nortestos- 1 mg l8. 2 28. 1 32. 7 0. 365 terone. 5 mg 36. 8 74. 7 48. l 0. 631 methyl-Mame titling: t3 13:2 58:2 8% temne- 5.555 mg- 15.6 39. 4 82.8 o. 422 e i t'a' t: i3 i313 iii 8:553 stene'lm'lwdwl' 5 mg 19. 5 32. 6 40. 5 0. 457

1 Lf=ratio of the weight of the fresh levator aniXlO to the body weight.

These results show that l7a-methyl-A -5a-androstene- 113,17B-diol presents a clear anabolic action, equal or even slightly superior to those of 17u-methyl-testosterone and of 17a-ethyl-l9-nor-testosterone, all while presenting only a very weak androgenic eifect, quite similar to that of l7m-ethyl-l9-nor-testosterone and distinctly lower than that of 17a-methyl-testosterone. By comparison with 170: methyl l9 nor testosterone, the compound 17amethyI-A -Sa-andrOstene-I15,17,8-diol, subject of the invention, shows a lower anabolic effect at a dose of 5 mg, but it shows, on the other hand, a clearly less androgenic effect.

Determination of the toxicity l7a-methyl-A -5a-androstene-11,8,17B-diol, utilized in an aqueous suspension, was administered orally, to two groups of 10 female mice each of the Rockland strain, having an average weight of g., at doses of 50 mg./ kg. and 100 mg./kg. respectively, in a volume of 0.4 cc. per mouse Weighing 20 g.

No sign of intoxication or mortality was observed in the mice kept under observation over a period of 8 days.

17a-methyl-A -5a androstene 1 13,17 8 diol is, consequently, well tolerated by the mice in the acute toxicity test, at a dose of 100 mg./kg., orally administered.

The preceding examples are illustrative of the invention. It is to be understood however that other expedients may be employed without departing from the spirit of the invention or the scope of the appended claims.

We claim:

1. A 17a-methyl steroid of the formula 2. A process for the production of a 17a-methyl steroid of the formula which comprises the steps of reacting l7a-methyl-5aandrostane-SBJ1,8,17,3-triol with an organic hydrocarbon sulfonic acid chloride of the formula wherein R represents an organic hydrocarbon group having from 1 to 10 carbon atoms, in an organic solvent, subjecting the resulting compound of the formula on no 1 on, CH3

I it

wherein R has the above-assigned meaning, to the action of an alkaline agent in a solvent at elevated temperatures, and recovering said 17u-methyl steroid.

3. The process of claim 2 wherein said organic hydrocarbon sulfonic acid chloride in an organic solvent is tosyl chloride in pyridine.

4. The process of claim 2 wherein said organic hydrocarbon sulfonic acid chloride in an organic solvent is mesyl chloride in pyridine.

5. The process of claim 2 wherein said alkaline agent is a member selected from the group consisting of alkali metal hydroxide and alkali metal carbonate.

6. A process for the production of 17u-methyl-A -5uandrostene-llfi,l7,3-diol which comprises the steps of reacting 17a-methyl-5a-androstane-3B,l1,8,17,3-tri0l with tosyl chloride in pyridine, subjecting the 3fl-tosyloxy-l7amethyl-Sa-androstane-l1,3,1713-diol to the action of lithium carbonate in dimethylformamide at reflux temperature and recovering said 17a-methyl-A -5a-androstene-11 3,175- diol.

7. A sulfonic acid ester of the formula wherein R represents an organic hydrocarbon having from 1 to 10 carbon atoms.

8. 3fl-tosyloxy-l7a-methyl-5a-androstane-1 15,1713-diol. 9. A method for the treatment of anabolic deficiencies 7 w 8 in warm-blooded animals which comprises administering References Cited by the Examiner to the warm-blooded animal a daily dose of from 70 7/ kg. to 600 7/ kg. of a. 17a-methyl steroid of the formula Berkoz et Journal Chem" 8 (August) 1963, page 1977. /OH Harnik: Journal Org. Chem., vol. 28 (1963) pages HO 3387-3389.

CH CH;

3 LEWIS GOTTS, Primary Examiner. L 10 ELBERT L. ROBERTS, Examiner. 

9. A METHOD FOR THE TREATMENT OF ANABOLIC DEFICIENCIES IN WARM-BLOODED ANIMALS WHICH COMPRISES ADMINISTERING TO THE WARM-BLOODED ANIMAL A DAILY DOSE OF FROM 70 KG. TO 600 KG OF A 17A-METHYL STEROID OF THE FORMULA 